Glaucoma is a heterogeneous group of optic neuropathies that share certain clinical features. The loss of vision in glaucoma is due to the selective death of retinal ganglion cells in the neural retina that is clinically diagnosed by characteristic changes in the visual field, nerve fiber layer defects, and a progressive cupping of the optic nerve head (ONH). One of the main risk factors for the development of glaucoma is the presence of ocular hypertension (OHT), i.e., elevated intraocular pressure (IOP). An adequate IOP is needed to maintain the shape of the eye and to provide a pressure gradient to allow for the flow of aqueous humor to the avascular cornea and lens. IOP levels also may be involved in the pathogenesis of normal tension glaucoma (NTG), as evidenced by patients benefiting from IOP lowering medications. Once adjustments for central corneal thickness are made to IOP readings in NTG patients, many of these patients may be found to be ocular hypertensive.
The elevated IOP associated with glaucoma is due to elevated aqueous humor outflow resistance in the trabecular meshwork (TM), a small specialized tissue located in the iris-corneal angle of the ocular anterior chamber. Glaucomatous changes to the TM include a loss in TM cells and the deposition and accumulation of extracellular debris including proteinaceous plaque-like material. In addition, there are also changes that occur in the glaucomatous ONH. In glaucomatous eyes, there are morphological and mobility changes in ONH glial cells. In response to elevated IOP and/or transient ischemic insults, there is a change in the composition of the ONH extracellular matrix and alterations in the glial cell and retinal ganglion cell axon morphologies.
Primary glaucomas result from disturbances in the flow of intraocular fluid that has an anatomical or physiological basis. Secondary glaucomas occur as a result of injury or trauma to the eye or a preexisting disease. Primary open angle glaucoma (POAG), also known as chronic or simple glaucoma, represents the majority of all primary glaucomas. POAG is characterized by the degeneration of the trabecular meshwork, resulting in abnormally high resistance to fluid drainage from the eye. A consequence of such resistance is an increase in the IOP that is required to drive the fluid normally produced by the eye across the increased resistance.
Rho-associated, coiled-coil containing protein kinases, also known as Rho kinases or ROCKs, are effectors of the Rho family of small GTP-binding proteins (Rho GTPases). The Rho GTPase signaling pathway appears to play a role in regulating aqueous humor outflow, for example, by altering the cytoskeletal organization of trabecular meshwork (TM) and/or ciliary muscle (CM) cells. Small molecule inhibitors of Rho kinase cause reversible changes in TM cell morphology and cytoskeletal organization, decrease contractility of isolated CM tissue, and increase aqueous humor outflow facility in organ culture (Waki M. et al., Curr Eye Res. 22:470-4 (2001); Honjo M. et al., Invest Ophthalmol Vis Sci. 42:137-44 (2001); Rao P V. et al., Mol Vis. 11:288-97 (2005); Rao P V. et al., Invest Ophthalmol Vis Sci. 42:1029-37 (2001)). Similar effects are generated by expression of dominant negative Rho-binding domains. However, treatment with small molecule inhibitors of Rho kinase also causes vasodilation and conjunctival hyperemia. In addition, the efficacy of small molecule-based therapies is relatively short-lived requiring repeated dosing during each day and, in some cases, the efficacy decreases with time.
In view of the importance of ocular hypertension in glaucoma and the side effects of prior methods of treatment, it would be desirable to have an improved method of treating ocular hypertension.